title: Negative symptoms in schizophrenia--the remarkable impact of inclusion definitions in clinical trials and their consequences.
abstract: BACKGROUND
  Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus.
  
  
  OBJECTIVE
  We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms.
  
  
  METHODS
  Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome.
  
  
  RESULTS
  Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from "typical" trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics.
  
  
  CONCLUSIONS
  Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow.
authors.affiliation: Bar Ilan University, Ramat Gan, Israel. Electronic address: jonathan.rabinowitz@biu.ac.il.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rabinowitz
authors.forename: Nomi
authors.initials: N
authors.lastname: Werbeloff
authors.forename: Ivo
authors.initials: I
authors.lastname: Caers
authors.forename: Francine S
authors.initials: FS
authors.lastname: Mandel
authors.forename: Virginia
authors.initials: V
authors.lastname: Stauffer
authors.forename: François
authors.initials: F
authors.lastname: Menard
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Kinon
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016208:Databases, Factual / Q000706:statistics & numerical data; D006801:Humans; D018579:Patient Selection; D012559:Schizophrenia / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents
keywords: Antipsychotic trials; Negative symptoms